Transdermal therapeutic system containing hormones and crystallization inhibitors

ABSTRACT

A transdermal therapeutic system in plaster form for controlled release of oestradiol in combination with norethisterone acetate, comprising a backing layer, a reservoir supersaturated with active ingredients which is attached to said backing layer and prepared using polyacrylate pressure-sensitive adhesives and crystallization inhibitors, and a detachable protective layer, is characterized in that the crystallization inhibitor is an amino-containing polymer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Section 371 National Stage application ofInternational Application No. PCT/EP99/03922, filed on Jun. 8, 1999,which claims priority of German Application No. 198 28 273.7, filed Jun.25, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a transdermal therapeutic system (TTS) forcontrolled release of oestradiol in combination with norethisteroneacetate to the human skin.

2. Description of the Prior Art

Oestradiol in combination with norethisterone acetate has a very lowsaturation solubility in the auxiliaries normally used to formulatetransdermal therapeutic systems, such as polyacrylate adhesives,tackifiers, plasticizers and absorption improvers. As a result, thecapacity to load a TTS with dissolved active ingredient is greatlylimited, and/or, in the case of supersaturation, unwantedcrystallization occurs during storage. Consequently, the proportion ofdissolved active ingredients in the matrix is reduced, which has anadverse effect on their release.

For combined preparations comprising oestradiol and norethisteroneacetate, administration forms have been developed in which the activeingredients in a transdermal therapeutic system are contained inseparate areas. However, manufacturing such TTSs is very expensive.

Accommodating drying agents together with transdermal therapeuticsystems in the primary packaging reduces the risk of recrystallizationbut is far from straightforward.

DE-A 43 36 557 describes an active substance transdermal therapeuticsystem based on a pressure-sensitive adhesive which comprises rosinesters. It is prepared by kneading the components in the melt attemperatures between 100 and 140° C. and then carrying out coating. Suchhigh temperatures in the preparation of pharmaceutical forms carry withthem the risk that degradation products may be formed in an unacceptablyhigh amount.

WO 95/30409 describes a topical polymer release system for theadministration of certain active ingredients by means of apropellantless aerosol pump. The absence of adhesives is emphasized asan advantage. Additional components used include crystallizationinhibitors/stabilizers and/or penetration enhancers such as substitutedcyclodextrins, Transcutol, urea and isoterpenes; the active substancecombination of oestradiol and norethisterone acetate is not claimed.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to provide a stable, i.e.recrystallization-free, plaster comprising the active ingredientsoestradiol and norethisterone acetate.

It has surprisingly been found that in a transdermal therapeutic systemhaving the features of the main claim this object is achieved by the useof an amino-containing polymer as crystallization inhibitor.Advantageous crystallization inhibitors used are polymers based on butylmethacrylate, 2-dimethylaminoethyl methacrylate and methyl methacrylate,preferably in a molar ratio of 1:2:1, polyaminoamides,polyaminoimidazolines, polyetherurethaneamines, polyamines andpolyglucosamines.

It has been found that the crystallization inhibitors are particularlysuitable in a proportion of from 0.05 to 30% by weight.

The formation of hydrogen bonds between the basic groups of thecrystallization inhibitor and the mobile hydrogen atoms of theoestradiol molecule results in immobilization of oestradiol.Consequently, the concentration of freely mobile oestradiol in thematrix is reduced and crystallization prevented.

The pressure-sensitive adhesive reservoir contains oestradiol andnorethisterone acetate in a weight ratio of from 1:2 to 1:15, preferablyfrom 1:3 to 1:7, and in an overall concentration of up to 25% by weight.

The reservoir may comprise a constituent from the group consisting ofageing inhibitors, plasticizers, antioxidants and absorption improvers,the plasticizer being used in a concentration of from 0 to 5% by weightand the ageing inhibitor in a concentration of from 0.1 to 2% by weight.

Suitable ageing inhibitors, plasticizers, antioxidants and absorptionimprovers are known to the person skilled in the art and are described,for example, in DE 37 43 946.

In order to be able to apply the transdermal therapeutic system to theskin it is necessary for the system to have pressure-sensitive adhesiveproperties. In order to impart these properties to the transdermaltherapeutic system of the invention use is made of polyacrylatepressure-sensitive adhesives in the form of solutions in organicsolvents, known as solvent-based pressure-sensitive adhesives.

It is also possible to use polyacrylate pressure-sensitive adhesives inthe form of aqueous dispersions.

Also suitable are hot-melt pressure-sensitive adhesives. These are freeof solvent or dispersant and are applied from the melt.

UV-crosslinkable acrylate pressure-sensitive adhesives are alsosuitable. These are solvent-free and are applied using the conventionalcoating techniques. Subsequently, the polymer chains are crosslinked byirradiation with UV light. This is necessary in order to give thepressure-sensitive adhesive adequate cohesion.

The reservoir of the transdermal therapeutic system may consist of aplurality of layers each with the same or different concentrations ofactive ingredient.

The layer thickness of the reservoir is from 0.02 mm to 0.500 mm butpreferably from 0.030 mm to 0.200 mm.

The reservoir can be provided with an additional pressure-sensitiveadhesive layer and/or with a pressure-sensitive adhesive margin. Thisbecomes necessary when the pressure-sensitive adhesive properties of thereservoir itself are inadequate.

The transdermal therapeutic system of the present invention is intendedfor therapeutic applications in human medicine.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The invention is illustrated below on the basis of examples.

EXAMPLE 1

-   155.08 g of Durotak 387-2287 (National Starch) (polyacrylate    pressure-sensitive adhesive (PSA)) and-   4.81 g of Eudragit E 100 (Röhm) (polyacrylate) are homogenized with    stirring and, together with a suspension of-   2.17 g of Eutanol G (Caesar und Loretz) (long-chain fatty alcohol)-   0.03 g of aluminium acetylacetonate (Merck-Schuchardt),-   1.29 g of oestradiol hemihydrate and-   8.33 g of norethisterone acetate, are dissolved in a solvent mixture    comprising-   27.98 g of ethyl acetate and-   27.97 g of ethanol.

The resultant adhesive solution is applied to a detachable protectivelayer of Hostaphan RN 100, siliconized on both sides, to give afterdrying an active substance matrix having a coated weight of 96.3 g/m². Abacking layer impermeable to the active ingredients (0.015 mm thickpolyester film) is laminated onto the resultant matrix. Subsequently,TTS patches measuring 40 cm₂ are punched out.

EXAMPLES 2-7 AND COMPARISON

Preparation takes place as described under Example 1 but with thestarting materials and amounts specified in Table 1.

TABLE 1 Composition (g) Example Comparison 2 3 4 5 6 7 Durotak 387-424.31 132.84 162.25 171.50 171.50 162.25 171.50 2287 Oestradiol 3.371.34 1.34 1.34 1.34 1.34 1.34 hemihydrate Norethisterone 21.60 8.65 8.658.65 8.65 8.65 8.65 acetate Eutanol G 5.59 2.25 2.25 2.25 2.25 2.25 2.25Al acetyl- 1.36 0.054 0.054 0.054 0.054 0.054 0.054 acetonate Ethylacetate 36.48 29.28 27.11 27.11 29.28 27.11 Ethanol 36.48 29.28 27.1127.11 29.28 27.11 Methyl ethyl 134.79 — — — — — — ketone EUREDUR 145 — —20.0 — — — — — A curing agent for epoxide resins EUREDUR 125 — — — 5.0 —— — — A curing agent for epoxide resins EUREDUR 250 — — — — 0.5 — — — Acuring agent for epoxide resins EUREDUR 43 — — — — — 0.5 — — A curingagent for epoxide resins EUREDUR 27 — — — — — — 5.0 — A curing agent forepoxide resins EUREDUR 10 — — — — — — — 0.5 A curing agent for epoxideresins

The test for signs of recrystallization was conducted microscopically intransmitted light at 40 times magnification. The results are set out inTable 2.

TABLE 2 Recrystallization Crystals per 40 cm² following storage forExample 1 3 months at 40° C. Comparison 154 1 0 2 0 3 0 4 0 5 0 6 0 7 0

As evident from Table 2 the addition of crystallization inhibitors givestransdermal therapeutic systems which are free from crystallization, incontrast to the comparative example (without crystallization inhibitor)in which there is considerable crystallization within a period of 3months.

The invention has been described with particular emphasis on thepreferred embodiments, but variations and modifications within thespirit and scope of the invention may occur to those skilled in the artto which the invention pertains.

1. A transdermal therapeutic system in plaster form for controlledrelease of oestradiol in combination with norethisterone acetate,comprising: a backing layer; a reservoir supersaturated with activeingredients, said active ingredients being oestradiol and norethisteroneacetate, said reservoir being attached to said backing layer and beingprepared by mixing polyacrylate pressure-sensitive adhesives,crystallization inhibitor(s), and said active ingredients wherein thecrystallization inhibitor(s) is amino group-containing polymer selectedfrom the group consisting of polyaminoamides, polyaminoimidazolines,polyetherurethaneamines and polyglucosamines; and a detachableprotective layer.
 2. A transdermal therapeutic system according to claim1, wherein the reservoir comprises at least one crystallizationinhibitor in proportion of from 0.05 to 30% by weight.
 3. A transdermaltherapeutic system according to claim 1, wherein the reservoir comprisesoestradiol and norethisterone acetate in a weight ratio of from 1:2 to1:15, and in an overall concentration of up to 25% by weight.
 4. Atransdermal therapeutic system according to claim 1, wherein thereservoir includes a constituent from the group consisting of aginginhibitors, plasticizers, antioxidants and absorption improvers, theplasticizers being used in a concentration of 0 to 5% by weight and theaging inhibitor in a concentration of 0.1 to 2% by weight.
 5. Atransdermal therapeutic system according to claim 1, wherein thepressure-sensitive adhesive is selected from the group consisting of asolvent-based adhesive, a dispersion adhesive, a hot-melt adhesive and aUV-crosslinkable adhesive.
 6. A transdermal therapeutic system accordingto claim 1, wherein the reservoir consists of at least two layers.
 7. Atransdermal therapeutic system according to claim 1, wherein thereservoir has a layer thickness of 0.02 mm to 0.500 mm.
 8. A transdermaltherapeutic system according to claim 1, wherein the reservoir isprovided with an additional pressure-sensitive adhesive layer.
 9. Atransdermal therapeutic system according to claim 3, wherein thereservoir comprises oestradiol and norethisterone acetate in a weightratio of from 1:3 to 1:7.
 10. A transdermal therapeutic system accordingto claim 7, wherein the reservoir has a layer thickness of 0.030 to0.200 mm.
 11. A transdermal therapeutic system according to claim 8,wherein the reservoir is provided with a pressure-sensitive adhesivemargin.
 12. A transdermal therapeutic system according to claim 1,wherein the reservoir is provided with a pressure-sensitive adhesivemargin.
 13. A method for providing a transdermal therapeutic system fortherapeutic applications of a drug comprising oestradiol in combinationwith norethisterone in human medicine, said method comprising: applyingsaid transdermal therapeutic system to the skin of a patient; andcontrolling the release of oestradiol in combination with norethisteroneacetate to the human skin by providing a reservoir in said transdermaltherapeutic system, said reservoir being supersaturated with the activeingredients, oestradiol and norethisterone acetate, and being attachedto a backing layer, wherein said reservoir comprises at least one aminogroup-containing polymer as a crystallization inhibitor, and at leastone adhesive consisting of a polyacrylate pressure-sensitive adhesives;wherein said crystallization inhibitor is an amino group-containingpolymer selected from the group consisting of polyaminoamides,polyaminoimidazolines, polyetherurethaneamines, and polyglucosamines andwherein hydrogen bonds are created between basic groups of said at leastone amino group-containing crystallization inhibitor and the mobilehydrogen atom of the oestradiol to immobilize the oestradiol to reducethe concentration of freely mobile oestradiol in the matrix to preventcrystallization.